Tuberculosis 1 Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies

Transcription

1 Tuberculosis 1 Tuberculosis: progress and advances in development of new drugs, treatment regimens, and host-directed therapies Simon Tiberi, Nelita du Plessis, Gerhard Walzl, Michael J Vjecha, Martin Rao, Francine Ntoumi, Sayoki Mfinanga, Nathan Kapata, Peter Mwaba, Timothy D McHugh, Giuseppe Ippolito, Giovanni Battista Migliori, Markus J Maeurer, Alimuddin Zumla Tuberculosis remains the world s leading cause of death from an infectious disease, responsible for an estimated deaths annually. WHO estimated cases of rifampicin-resistant tuberculosis in 2016 of which were multidrug resistant (MDR), with less than 50% survival after receiving recommended treatment regimens. Concerted efforts of stakeholders, advocates, and researchers are advancing further development of shorter course, more effective, safer, and better tolerated treatment regimens. We review the developmental pipeline and landscape of new and repurposed tuberculosis drugs, treatment regimens, and host-directed therapies (HDTs) for drug-sensitive and drug-resistant tuberculosis. 14 candidate drugs for drug-susceptible, drug-resistant, and latent tuberculosis are in clinical stages of drug development; nine are novel in phase 1 and 2 trials, and three new drugs are in advanced stages of development for MDR tuberculosis. Specific updates are provided on clinical trials of bedaquiline, delamanid, pretomanid, and other licensed or repurposed drugs that are undergoing investigation, including trials aimed at shortening duration of tuberculosis treatment, improving treatment outcomes and patient adherence, and reducing toxic effects. Ongoing clinical trials for shortening tuberculosis treatment duration, improving treatment outcomes in MDR tuberculosis, and preventing disease in people with latent tuberculosis infection are reviewed. A range of HDTs and immune-based treatments are under investigation as adjunctive therapy for shortening duration of therapy, preventing permanent lung injury, and improving treatment outcomes of MDR tuberculosis. We discuss the HDT development pipeline, ongoing clinical trials, and translational research efforts for adjunct tuberculosis treatment. Introduction In 2016, there were an estimated 10 4 million cases of tuberculosis with 1 67 million deaths, making tuberculosis the ninth leading cause of death worldwide. 1 The 2017 WHO Global Tuberculosis Report estimated cases of multidrug-resistant (MDR) tuberculosis, with less than 50% survival in patients who received recommended WHO treatment regimens. 1 6 The Report reveals the dire need for new therapies and approaches for improving tuberculosis treatment delivery and management outcomes. Many challenges remain in developing optimal tuberculosis treatment regimens. 7 Concerted efforts of stakeholders, advocates, and researchers are advancing the further development of shorter course, more effective, safer, and better tolerated treatment regimens. Only three novel drugs are in advanced stages of development for MDR tuberculosis, and nine are being assessed in phase 1 and 2 trials. In addition to new drugs, an array of immune-based treatments and host-directed therapies are under development aimed at eliminating Mycobacterium tuberculosis infection, shortening the duration of treatment, preventing permanent lung injury, and preventing development of new drug resistance. This Series paper provides updates on advances and progress in the development pipeline of new and repurposed tuberculosis drugs and host-directed therapies, addressing the unmet needs of treatment management for patients with tuberculosis (panel 1). In this Series paper we review ongoing clinical trials for shortening tuberculosis treatment, improving treatment outcomes in MDR tuberculosis, and preventing disease in people with latent tuberculosis infection. We also discuss Key messages Lancet Infect Dis 2018 Published Online March 23, S (18) This is the first in a Series of two papers about tuberculosis See Online/Comment S (18) See Online/Series S (18) Division of Infection, Royal London Hospital, Barts Health NHS Trust, London, UK (S Tiberi MD); South African Department of Science and Technology, and National Research Foundation Centre of Excellence for Biomedical Tuberculosis Research, Stellenbosch University, Tuberculosis caused 1 67 million deaths in Drug-resistant tuberculosis is a now a major threat to global health security. WHO recommended treatments can only cure 50% of multidrug-resistant (MDR) tuberculosis and 30% of patients with extensively drug resistant tuberculosis. Newer, more potent drugs are required that could build a universal regimen for effectively treating and reducing the duration of drug-resistant and drug-sensitive tuberculosis. Concerted efforts of stakeholders, advocates, and researchers are slowly advancing the development of shorter course, more effective, safer, and better tolerated treatment regimens. 14 candidate drugs for drug-susceptible, drug-resistant, and latent tuberculosis are in the clinical stages of drug development. The new diarylquinoline (bedaquiline) and nitroimidazoles (pretomanid, delamanid) provide hope for an all-oral regimen for MDR tuberculosis. A range of host-directed therapies (HDTs) are being developed as adjuncts to drug treatment to hasten elimination of Mycobacterium tuberculosis infection, shorten the duration of treatment, reduce excessive inflammation, minimise permanent lung damage, and prevent new drug resistance. Access to the new drugs and conduct of clinical trials are hampered by high costs. Development of new medicines and regimens should be twinned with funder investments to ensure that these medicines are affordable, effective, safe, and reach the people who need them. A substantial increase in political and funder attention is required to increase the inadequate funding portfolio for new drugs and HDTs. Published online March 23,

2 Cape Town, South Africa (Prof G Walzl FRCP, N du Plessis PhD); Centers for Disease Control and Prevention Tuberculosis Trials Consortium Core Science Group, Veterans Affairs Medical Center, Washington, DC, USA (M J Vjecha MD); Champalimaud Foundation, Lisbon, Portugal, and Krankenhaus Nordwest, Frankfurt, Germany (Prof M Maeurer FRCP, M Rao PhD); Fondation Congolaise pour la Recherche Medicale, and Faculte des Sciences et Techniques, specific issues regarding safety and toxicity, and drug drug interactions The organisations TB Alliance and WHO Stop TB Partnership provide more information about research and treatment of tuberculosis around the world. Progress in the development of new drugs and treatment regimens In the past 5 years, development of several new and repurposed antituberculosis drugs has accelerated with the approval of the first new antituberculosis drug in 35 years The advent of diarylquinoline and the nitroimidazoles provides hope for an oral pan-tuberculosis regimen, based on potent specific drugs for which Panel 1: Unmet needs of tuberculosis treatment 8 A potent and cheap pan-tuberculosis treatment regimen that is well tolerated and can treat both drug-susceptible and drug-resistant disease without cumulative toxic drug effects or increased relapse rates Treatment regimens that can improve survival rates in patients with drug-resistant tuberculosis and with Mycobacterium tuberculosis HIV coinfection A treatment regimen that is of short duration with minimal side-effects and low pill burden to improve patient acceptance and adherence, and reduce loss to follow-up and treatment failure Nearly 50% of patients treated for pulmonary tuberculosis develop long-term lung damage and functional disability (chronic cough, breathlessness, impaired lung function, and reduced longevity, despite treatment success); new strategies are required to prevent, manage, and perhaps reverse the loss in lung function Improved treatments for latent M tuberculosis infections due to drug-resistant strains Adjunct host-directed therapies with tuberculosis drug treatment to minimise or prevent lung injury and long-term functional impairment Improved biomarkers to predict response to treatment, risk of relapse, assure cure, and accelerate drug development Better supply chain and delivery of drugs to the patients that need them as of 2017, very few patients with drug-resistant tuberculosis have access to effective treatment Increased funder investments into development and assessment of new drugs, host-directed therapies, and biomarkers Preclinical development Early stage Caprazene nucleoside CPZEN-45* Cyclopeptide SATB082* Spectinamide 1810* Gyrase inhibitor SPR-720 (pvxc-486) Pyrazolopyridine carboxamide TB-47 DC-159a GMP or GLP tox BTZ 043* TBAJ-587 TBI-166 TBI-223 GSK 286* OPC * Q203* GSK070* Contezolid MRX- 4/MRX TBA7371* Clinical development Phase 1 Phase 2 Phase 3 Delpazolid (LCB ) Sutezolid (PNU100480) SQ109* PBTZ169* Nitroimidazole Diarylquinoline Rifamycin Oxazolidinone Bedaquiline (TMC-207) Delamanid (OPC-67683) Pretomanid (P A-824) Rifapentine Benzothiazinone Imidazopyridine amide Fluoroquinolone Figure: Global new tuberculosis drug development pipeline Adapted from Stop TB Partnership s Working Group on New TB Drugs (October, 2017) with permission. 17 *New chemical class. GMP=good manufacturing practice. New to phase. GLP tox=good laboratory practice toxicology studies. resistance is weak or non-existent. The line-up of the tuberculosis drug development pipeline, as of December, 2017, is shown in the figure. The class of drugs, their mechanisms of action, trial phase, and relevant sponsors are presented in table PBTZ169 is now in phase 2 early bactericidal activity trials. A new compound, Q203, was assessed in a phase 1 trial completed in 2017, and TBA7371 entered a phase 1 trial in SQ109 appears to be sterilising in vitro but should not be used with rifampicin, which substantially reduces its levels. Interim results from a double-blind placebocontrolled trial in Russia, in patients with MDR tuberculosis, showed that at 24 weeks 80% of patients receiving SQ109 plus optimised background regimen were sputum negative compared with 61% patients receiving placebo plus regimen (p=0 048). 19 However, with these advances there have also been some setbacks. Sutezolid yielded promising phase 2 trial results, but some stage 1 studies needed to be repeated because of licensing issues. AZD5847 and TBA 354 showed no activity in phase 1 studies and are associated with neurotoxicity candidate drugs for drug-susceptible, MDR, and latent tuberculosis are in the clinical stages of drug development; nine are novel, and three have been approved (appendix). Drug-susceptible tuberculosis Treatments for patients with drug-susceptible tuberculosis last at least 6 months, requiring the patient to take on average ten pills a day during the intensive phase. WHO recommends treatment for drug-susceptible tuberculosis with an initial 2-month intensive phase (isoniazid, rifampicin, pyrazinamide, and ethambutol daily), continued by dual therapy isoniazid and rifampicin for the last 4 months. The whole course of treatment for the disease is around US$20, and treatment success in programmatic conditions is approximately 85%. Apart from the efficacy and economic value, the regimen is lengthy, hepatotoxic, and not well tolerated by a substantial proportion of patients prescribed the medication. 4-month standard regimens are, so far, only recommended by the American Thoracic Society for patients who are sputum smear and culture negative with minimal pulmonary disease. 11 Table 2 summarises the ongoing drug trials aimed at shortening and simplifying regimens for drugsusceptible tuberculosis and improving management, including increasing patient adherence. Studies investigating the optimisation of the use of approved drugs with improved formulations and pill counts are also ongoing. 21 More palatable fixed-dose combination tablets are now available for paediatric use, simplifying dosing in children weighing less than 25 kg, 22 while improving drug delivery and drug adherence. 23,24 Efforts are also being made to render the standard quadruple regimens less toxic. One study 25 showed that liver toxicity was reduced when methionine 2 Published online March 23,

3 Target Sponsors Phase Notes Diarylquinoline Bedaquiline ATP synthase Janssen, TB Alliance, NIAID, SAMRC, 3 Conditional marketing approval The Union, Unitaid, USAID Nitroimidazole Delamanid Cell wall synthesis and cell respiration Otsuka, NIAID, Unitaid 3 Conditional marketing approval Pretomanid Cell wall synthesis and cell respiration TB Alliance 3 Potent bactericidal and sterilising activity in mouse models Oxazolidinone Sutezolid Protein synthesis (23s ribosome) Pfizer, then Sequella, NIAID, Medicines Patent Pool, TB Alliance 2a Renewed commercial development, more potent and less toxic than linezolid, phase 2 trials starting in 2018 Delpazolid Protein synthesis (23s ribosome) LegoChem Biosciences 2 Results in phase 2 safety, EBA study expected later in 2018 Contezolid Protein synthesis (23s ribosome) MicuRX Pharmaceuticals 1 Potentially less toxic than linezolid 1,2-ethylene diamine SQ109 Cell wall synthesis (MmpL3) Sequella, PanACEA, Infectex 2 No efficacy in PanACEA phase 2 trial with high-dose rifampicin (NCT ), results from trial in Russia in 2018 DprE1 inhibitor PBTZ169 Cell wall synthesis Nearmedic, im4tb, BMGF 2 Benzothiazinone, synergy with bedaquiline and clofazimine OPC Cell wall synthesis Otsuka, BMGF 1 Potent, synergy with delamanid TBA7371 Cell wall synthesis Eli Lilly, Foundation for Neglected Disease Research, TB Alliance 1 Potential to shorten treatment for all forms of tuberculosis; phase 1 trial began August, 2017 (NCT ) BTZ 043 Cell wall synthesis University of Munich, PanACEA 1 Benzothiazinone, synergy with rifampicin, low toxicity, no hepatic enzyme interactions Imidazopyridine Q203 Cytochrome QcrB and cell respiration Qurient, Infectex, PanACEA 1 Phase 1 trial underway (NCT ); PanACEA will open phase 2 trial mid-2018 to study optimal dose of rifampin and pyrazinamide in combination with Q203 Riminophenazine TBI-166 Ion transport and cell respiration Institute of Materia Medica, TB 1 Same class as clofazamine, with less toxicity Alliance Oxaborole GSK 070, GSK Protein synthesis (leucyl-trna synthetase) GlaxoSmithKline 1 Phase 2a studies to begin mid-2018 Adapted from Treatment Action Group report. 20 NIAID=National Institute of Allergy and Infectious Diseases (USA). SAMRC=South Africa Medical Research Council. The Union=International Union Against Tuberculosis and Lung Disease. USAID=US Agency for International Development. EBA=early bactericidal activity. PanACEA=Pan African Consortium for the Evaluation of Antituberculosis Antibiotics. im4tb=innovative Medicines for Tuberculosis Foundation. BMGF=Bill & Melinda Gates Foundation. Table 1: Development pipeline of new drugs for tuberculosis Universite M Ngouabi, Brazzaville, Republic of the Congo (Prof F Ntoumi FRCP); National Institute for Medical Research, Muhimbili Medical Research Centre, Dar es Salaam, Tanzania (Prof S Mfinanga PhD); UNZA-UCLMS Research and Training Programme, and Apex University, Lusaka, Zambia (Prof P Mwaba FRCP); Institute of Public Health, Ministry of Health, Lusaka, Zambia (N Kapata MPH); National Institute for Infectious Disease, L Spallanzani, Rome, Italy (Prof G Ippolito FRCP); World Health Organization Collaborating Centre for Tuberculosis and Lung Diseases, Maugeri Care and Research Institute, Istituto di Ricovero e Cura a Carattere Sceintifico, Tradate, Italy (Prof G B Migliori FRCP); Centre for Clinical Microbiology, Division of Infection and Immunity, University College London, London, UK (Prof T D McHugh PhD, Prof A Zumla FRCP); and National Institute of Health and Research Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK (Prof A Zumla) Correspondence to: Prof Sir Alimuddin Zumla, Division of Infection and Immunity, University College London, and National Institute of Health and Research Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London WC1E 6BT, UK a.i.zumla@gmail.com For more on TB Alliance see For more on Stop TB see See Online for appendix and vitamin B complex were added to the standard regimen. Research on rifampicin, which was introduced in the 1970s, is centred on determining the therapeutic window and assessing higher doses, which can achieve greater potency than lower doses. A phase 2 trial 26 showed that 20 mg/kg of rifampicin did not increase efficacy when compared with 10 mg/kg of rifampicin and 15 mg/kg of rifampicin together with isoniazid, ethambutol, and pyrazinamide. The PanACEA trial (NCT ), 27 the first multiarm multistage (MAMS) study of tuberculosis treatment, investigated 20 mg/kg and 35 mg/kg doses of rifampicin against a standard 10 mg/kg dose in patients with drug-susceptible tuberculosis. The 35 mg/kg dose was safe and the 35 mg/kg group had faster 8-week culture conversion times than both the 20 and 10 mg/kg groups, which might lead to shorter treatment durations. The addition of SQ109 or moxifloxacin did not achieve superiority over the standard quadruple regimen. The RIFASHORT (NCT ) and NC-006 STAND (NCT ) trials are focused on shortening the standard tuberculosis regimen, assessing the efficacy of high-dose rifampicin and an entirely new regimen. Rifapentine is being tested at a flat dose of 1200 mg daily in the Tuberculosis Trials Consortium (TBTC) Study 31/A5349; the phase 3 study will recruit 2500 patients Published online March 23,

4 NC-006 STAND (NCT ) (of original target of 1200), HIV and HIV+ adults APT (NCT ) 2 183, HIV adults Phase Study population Study groups Notes TBTC 31/A5349 (NCT ) , HIV and HIV+ adults and children ( aged 13 years ) SHINE (ISRCTN ) , HIV and HIV+ children (aged <16 years) with minimal disease RIFASHORT (NCT ) 3 800, HIV adults (aged 18 years) TRUNCATE-TB 2/3 900, HIV and HIV+ adults HIGHRIF 1 Extension (NCT ) 2 30, HIV adults STEP 2c 600, HIV adults NC-008 SimpliciTB (NCT ) 2c/3 300, HIV and HIV+ adults 4 months pretomanid (100 mg twice daily or 200 mg once daily), moxifloxacin, pyrazinamide daily, or 6 months pretomanid (100 mg twice daily), moxifloxacin, pyrazinamide daily, or 6 months pretomanid (200 mg once daily), moxifloxacin, pyrazinamide daily vs standard 6 month therapy 2 months pretomanid, rifabutin, isoniazid, pyrazinamide daily, and 1 month pretomanid, rifabutin, isoniazid daily, or 2 months pretomanid, rifampicin, isoniazid, pyrazinamide daily, and 1 month pretomanid, rifampicin, isoniazid daily vs 2 months isoniazid, rifampicin, pyrazinamide, ethambutol daily, and 1 month isoniazid, rifampicin daily 2 months isoniazid, rifapentine (1200 mg), pyrazinamide, and ethambutol daily, and 2 months isoniazid and rifapentine (1200 mg) daily, or 2 months isoniazid, rifapentine (1200 mg), pyrazinamide, and moxifloxacin daily, and 2 months isoniazid, rifapentine (1200 mg), and moxifloxacin daily vs standard 6 month therapy 2 months isoniazid, rifampicin (600 mg), pyrazinamide, and (in some) ethambutol daily, and 2 months isoniazid and rifampicin (600 mg) daily vs standard 6 month therapy 2 months isoniazid, rifampicin (1200 or 1800 mg), pyrazinamide, and ethambutol daily, and 2 months isoniazid and rifampicin (1200 or 1800 mg) daily vs standard 6 month therapy 2 months various new regimens vs standard 6 month therapy EBA safety, tolerability, pharmacokinetics study: 14 days rifampicin 50 mg/kg (3000 mg) daily 3 4 months isoniazid, rifampicin (600 mg), pyrazinamide, and Q203 daily, or 2 3 months isoniazid, rifampicin (high dose), pyrazinamide (high dose), and Q203 daily vs standard 6 month therapy 4 months bedaquiline, pretomanid, moxifloxacin, pyrazinamide vs standard 6 month therapy Opened February 2015 (paused October 2016 May 2017); accrual not resumed, results March 2018; TB Alliance Opened April, 2015 (paused October, 2016 May, 2017), results 2019; John Hopkins University, University of Cape Town Lung Institute Opened January, 2016; accrual to close at the end of 2018, results 2020; substudies include interactions of rifapentine and efavirenz, intensive pharmacokinetics and pharmacodynamics of rifapentine, and sputum biomarkers to predict outcomes; CDC TBTC, ACTG Opened third quarter of 2016, results 2020; treatment shortening strategy trial for children with minimal tuberculosis; India, Uganda, South Africa, and Zambia; BMRC Opened February, 2017, results January, 2020; St George s London, INTERTB Opened late 2017, results 2021; MAMS adaptive trial design; Thailand, Indonesia, Philippines, and Singapore; BMRC, NUS Opened September, 2017, results mid-2018; PanACEA Opens mid-2018, results 2021; adaptive trial design, examining new treatment backbones; PanACEA Opens August, 2018, results 2022; TB Alliance Standard 6 month therapy is 2 months isoniazid, rifampicin (600 mg for patients 50 kg and 450 mg for patients <50 kg), pyrazinamide, ethambutol daily, and 4 months isoniazid and rifampicin (600 mg for patients 50 kg and 450 mg for patients <50 kg) daily. CDC TBTC=Centers for Disease Control and Prevention Tuberculosis Trials Consortium. ACTG=AIDS Clinical Trials Group. MAMS=multiarm multistage trial. BMRC=British Medical Research Council. NUS=National University of Singapore. EBA=early bactericidal activity. PanACEA=Pan African Consortium for the Evaluation of Antituberculosis Antibiotics. Table 2: Ongoing and planned trials for drug-susceptible tuberculosis without HIV and those living with HIV with CD4 count above 100 cells per L. The first experimental group includes rifapentine and isoniazid for 4 months, with ethambutol and isoniazid for the first 2 months. The second experimental group replaces ethambutol with 4 months of moxifloxacin. The control group is the standard 6-month therapy. The TRUNCATE-TB 28 is a phase 2c open-label MAMS trial assessing the treatment of drug-susceptible tuberculosis in just 2 months, administering high-dose rifampicin, bedaquiline, delamanid, and linezolid in different combinations over five experimental groups. Treatment is extended to 12 weeks if study participants are still symptomatic or smear positive at week 8. Moxifloxacin is often used as a substitute for isoniazid or ethambutol in patients with monoresistant tuberculosis, or in patients with intolerability or contraindications (or both); however, moxifloxacin did not show potency in shortening regimens. Concomitant rifampicin reduces concentration of moxifloxacin in the blood by up to 31%, so higher doses of moxifloxacin might be required. 29 Concerns over QT prolongation have led to new studies to investigate the phenomenon patients from the OFLOTUB cohort (NCT ) 30 who had received quinolone-containing regimens contributed to the analysis of Fridericia s formula (QTcF) by treatment group in an extensive survey of QT prolongation. Neither a standard 6-month nor a 4-month gatifloxacin-based regimen seemed to carry a sizeable risk of QT prolongation in patients with newly diagnosed pulmonary tuberculosis. Gatifloxacin, a component of the Bangladesh regimen, is no longer on the WHO 4 Published online March 23,

5 essential drug list due to concerns over dysglycaemia, and it has been replaced in the shorter drug regimen by moxifloxacin, a drug which is known to prolong QTc. 30 Drug-resistant tuberculosis The taxonomy of antituberculosis drugs and their combinations is undergoing a rapid transformation as a result of new clinical trials data and meta-analyses. 31,32 The updated classification of new antituberculosis drugs by WHO (panel 2) guides physicians in constructing an effective drug-resistant treatment regimen that is patient specific, based on a minimum of four active drugs. 33 The regimen recommends two core drugs (a later-generation fluoroquinolone and an injectable aminoglycoside), and then the addition of other core drugs (eg, ethionamide or prothionamide, cycloserine or terizidone, linezolid, and clofazimine); if further drugs are required because of resistance or intolerance, then non-core drugs such as bedaquiline (especially if the patient is quinolone resistant) or delamanid should be added (combination of these two drugs is not recommended). Non-core drugs, such as para-aminosalicylic acid, carbapenems with clavulanate are reserved for patients with extensively drug-resistant (XDR) tuberculosis, with few therapeutic options. Pyrazinamide and ethambutol might be added, but they should not be counted as active drugs in the regimen. 33,34 A retrospective study 35 showed that the use of rifabutin was associated with improved treatment outcomes compared with no rifabutin treatment in patients with MDR tuberculosis. At least 20 new drugs are estimated to be required in phase 1 and 2 trials to ensure that a few progress to phase 3 assessment. With research investment being at its lowest amount since 2008, more resources are urgently required. 36 Table 3 summarises the ongoing drug trials aimed at shortening and simplifying regimens for drug-resistant tuberculosis. Three drugs are in phase 3: bedaquiline, delamanid, and pretomanid, of which delamanid and pretomanid are nitroimidazoles and unlikely to be used together. Nine candidates are in phase 1 and 2 studies; five of the drugs are from two classes (oxazolidinones and DprE1 inhibitors). Sutezolid and delpazolid are two newer generation oxazolidinones in early clinical trials that are anticipated to be just as effective as linezolid, but less toxic. Bedaquiline Bedaquiline (a diarylquinoline inhibiting ATP synthase), delamanid, and pretomanid are being investigated in some novel trials that are assessing their use as single drugs and in combination. By October, 2017, an estimated patients had received bedaquiline. 37 The WHO caution on the potential toxic effects of bedaquiline originated from the observation of ten unexpected late deaths in the bedaquiline group of the C208 phase 2b trial. 38 A systematic review 39 of published results from 1293 patients treated with bedaquiline reported that QT was greater than 450 ms for 35 (11%) of 329 people, and Panel 2: WHO categorisation of second-line antituberculosis drugs recommended for treatment of rifampicin-resistant and multidrug-resistant tuberculosis 33 Group A: fluoroquinolones Levofloxacin Moxifloxacin Gatifloxacin Group B: second-line injectable drugs Amikacin Capreomycin Kanamycin Streptomycin* Group C: other core second-line drugs Ethionamide or prothionamid Cycloserine or terizidone Linezolid Clofazimine Group D: add-on drugs (not part of the core multidrug-resistant regimen) D1 Pyrazinamide Ethambutol High-dose isoniazid D2 Bedaquiline Delamanid D3 Para-aminosalicylic acid Imipenem plus cilastatin (requires clavulanate) Meropenem (requires clavulanate) Amoxicillin plus clavulanate Thioacetazone *Caution: streptomycin is frequently resistant and unlikely to be active against drug-resistant tuberculosis. Thioacetazone can give serious adverse events. HIVnegative status needed before administering thioacetazone. Not to be administered to people who are HIV-positive. greater than 500 ms for 42 (3%) of 1293 people. In 44 (3%) of 1293 people, bedaquiline was stopped because of adverse events. In eight (1%) of 857 people, bedaquiline was discontinued specifically because of QT pro- longation. Of these eight participants, two were restarted on bedaquiline after temporary interruption. A retrospective study 40 of 428 patients with MDR tuberculosis, treated under programmatic conditions with bedaquiline, from across 15 countries, suggested that the risk of QT prolongation appears to be less than was initially envisaged. At the end of treatment, sputum smear conversion was observed in 126 (90%) of 140 patients and culture conversion in 191 (92%) of 208 patients. 25 (6%) of 428 patients discontinued the drug because of adverse events, with one death related to non-bedaquiline-related arrhythmia. Importantly, a Published online March 23,

6 significant clinical interaction appears to occur between rifamycins and bedaquiline, leading to a reduction in concentration of bedaquiline in the blood. As a result, the combined use of these two drugs are restricted in their use to treat drug-sensitive tuberculosis. Delamanid By October, 2017, 976 patients had received delamanid, made available by Otsuka, for a compassionate use programme that used approval processes of the European Respiratory Society WHO Tuberculosis Consilium, Médecins Sans Frontières (MSF), and others. 37,41,42 The Otsuka proprietary delamanid studies yielded consistent favourable outcomes (eg, sputum smear and conversion): phase 2 trial 204, 143 (74%) of 192 people; 43 phase 3 trial 213, 276 (81%) of 339 people; 44 and programmatic use in Latvia, 17 (84%) of 19 people. 45 Results of these compassionate use programmes are encouraging, with 53 (80%) of 66 patients achieving sputum culture conversion. 46 The efficacy and safety of the use of Phase Study population Study groups Notes Otsuka Trial 213 (NCT ) STREAM Stage 1 (ISRCTN ) 3 511, HIV- adults (aged 18 years) 3 424, HIV and HIV + adults NC-005 (NCT ) 2b 60, HIV- adults (aged 18 years) OPTI-Q (NCT ) 2 100, HIV and HIV + adults NC-006 STAND (NCT ) 3 13 (of original target of 300), HIV and HIV+ children (aged 14 years) NiX-TB (NCT ) (of original target of 300), HIV and HIV + adults NExT-5001 (NCT ) MDR-END (NCT ) STREAM Stage 2 (NCT ) Janssen C211 (NCT ) ACTG A5343 DELIBERATE (NCT ) endtb (NCT ) TB-PRACTECAL (NCT ) 2/3 300, HIV and HIV + adults 2 238, HIV and HIV + adults , HIV and HIV + adults 2 60, HIV- adults (aged 18 years) 2 84, HIV and HIV + adults 3 750, HIV and HIV + adults 2/3 630, HIV and HIV + adults 2 months delamanid (100 mg twice daily) and 4 months delaminid (200 mg daily) plus OBR vs 6 months placebo plus OBR 4 months daily moxifloxacin, clofazimine, pyrazinamide, ethambutol, isoniazid (high dose), kanamycin (daily for 3 months, then 3 times per week), prothionamide, and 5 months of moxifloxacin, clofazimine, pyrazinamide, ethambutol daily Serial sputum culture counts: 8 weeks bedaquiline (200 mg daily), pretomanid (200 mg daily), moxifloxacin, pyrazinamide, single arm study with long follow-up 6 months levofloxacin (14, 17, or 20 mg/kg/d) plus OBR vs 6 months levofloxacin (11 mg/kg/d) plus OBR 6 months pretomanid (200 mg), moxifloxacin, pyrazinamide daily, single arm study 6 months bedaquiline (200 mg daily for 2 weeks then 200 mg three times weekly), pretomanid (200 mg daily), linezolid (600 mg twice daily), single arm study 6 9 months bedaquiline, linezolid, levofloxacin, pyrazinamide, and either high-dose isoniazid or ethionamide or terizidone daily (all oral) vs 6 8 months kanamycin, moxifloxacin, pyrazinamide, ethionamide, terizidone daily, and months moxifloxacin 9 or 12 months delamanid, levofloxacin (750 or 1000 mg), linezolid (600 mg daily for 2 months, 300 mg daily thereafter) vs local regimen 9 months moxifloxacin, clofazimine, ethambutol, pyrazinamide daily, with initial 2 months isoniazid, kanamycin, prothionamide daily, or 9 months bedaquiline, clofazimine, ethambutol, levofloxacin, pyrazinamide daily, with initial 2 months isoniazid (high dose), prothionamide daily (all oral), or 6 months bedaquiline, clofazimine, levofloxacin, pyrazinamide daily, with initial 2 months isoniazid (high dose) and kanamycin vs month local regimen Pharmacokinetics, safety, dose-range 6 months bedaquiline (daily for 2 weeks, then 3 times a week) plus OBR, single arm study Pharmacokinetics, QTC 6 months bedaquiline daily plus OBR, or 6 months delamanid daily plus OBR, or 6 months bedaquiline and delamanid daily plus OBR 9 months bedaquiline, linezolid, moxifloxacin, pyrazinamide daily, or 9 months of bedaquiline, linezolid, clofazimine, levofloxacin, pyrazinamide daily, or 9 months of bedaquiline, linezolid, delamanid, levofloxacin, pyrazinamide daily, or 9 months of delamanid, linezolid, clofazimine, levofloxacin, pyrazinamide daily, or 9 months of delamanid, clofazimine, moxifloxacin, pyrazinamide daily vs local regimen 6 months bedaquiline, pretomanid, moxifloxacin, linezolid daily, or 6 months bedaquiline, pretomanid, linezolid, clofazimine daily, or 6 months bedaquiline, pretomanid, linezolid daily (all oral) vs local regimen Opened September 2011, completed June, 2016, preliminary findings presented at IUATLD October, 2017, confirm efficacy with less toxicity, results mid-2018; Otsuka Opened 2012, closed to accrual June, 2015, preliminary findings presented at IUATLD October, 2017, results mid-2018; IUATLD, BRMC, USAID Opened November, 2014, preliminary findings presented at CROI, 2017, results mid-2018; TB Alliance Opened January, 2015, results mid-2018; South Africa, Peru; NIAID, Boston University, CDC TBTC Opened February, 2015, paused October, 2016 May, 2017, accrual not resumed, results March, 2018; TB Alliance Opened March, 2015, preliminary findings presented at CROI, 2017, accrual closed November, 2017, with opening of NC-007 XeNiX trial; TB Alliance Opened October, 2015, results January, 2019; University of Cape Town Opened January, 2016, results December, 2019; Korea Opened April, 2016, results April, 2021; IUATLD, BMRC, USAID, TB Alliance Opened May, 2016, results March 2021; India, Philippines, Russia, South Africa; Janssen Opened August, 2016, results 2019; ACTG Opened December, 2016, results September, 2020; Georgia, Kazakhstan, Kyrgyzstan, Lesotho, Peru; MSF, Partners in Health Opened January, 2017, results March, 2021; Belarus, South Africa, Uzbekistan; MSF (Table 3 continues on next page) 6 Published online March 23,

7 (Continued from previous page) Phase Study population Study groups Notes IMPAACT P1108 (NCT ) NC-007 ZeNiX (NCT ) IMPAACT 2005 (NCT ) 2 72, HIV and HIV + children (aged <18 years) 3 180, HIV and HIV+ adults and children (aged 14 years) 1/2 48, HIV and HIV + children (aged <18 years) ACTG A5356 2a 240, HIV and HIV + adults NC-008 SimpliciTB (NCT ) 3 150, HIV and HIV + adults Pharmacokinetics, safety, dose-range 6 months bedaquiline (daily for 2 weeks, then 3 times a week) plus OBR, single arm study 2 or 6 months linezolid (600 or 1200 mg daily, double-blinded), bedaquiline (200 mg daily for 2 weeks, then 100 mg daily), and pretomanid (200 mg daily) Pharmacokinetics, safety 6 months delamanid (100 mg twice daily) plus OBR, single arm study 6 months delamanid (100 mg twice daily), linezolid (300 or 600 mg daily or 1200 mg every other day) plus OBR (oral) vs 6 months delamanid (100 mg twice daily) plus OBR (injectable) 6 months bedaquiline, pretomanid, moxifloxacin, pyrazinamide daily, single arm study Opened June, 2017, results June, 2020; Haiti, India, South Africa; IMPAACT Opened November, 2017, results January, 2021 Opened January, 2018, results April, 2021; Botswana, India, South Africa, Tanzania; IMPAACT Opens August, 2018; ACTG Opens August, 2018, results March 2022; TB Alliance OBR= optimised background regimen. IUATLD=International Union against Tuberculosis and Lung Disease. BMRC=British Medical ResearchCouncil. USAID=United States Agency for International Development. CROI=Conference on Retroviruses and Opportunistic Infections. MSF=Médecins sans Frontières. NIAID=National Institute of Allergy and Infectious Diseases (US National Institutes of Health). CDC TBTC=Centers for Disease Control and Prevention Tuberculosis Trials Consortium. ACTG=AIDS Clinical Trials Group. IMPAACT=International Maternal Pediatric Adolescent AIDS Clinical Trials Network. Table 3: Ongoing and planned treatment trials for drug-resistant tuberculosis delamanid in children older than 6 years is under investigation through several studies: the Otsuka Trial 233 (NCT ) is a 6-month pharmacokinetic and safety study in all paediatric weight groups, and results are expected in 2020; results of the Otsuka Trial 232, (NCT ) with 18-day pharmacokinetic and safety in different groups aged 0 17 years, are due out in ,47,48 Results of the first phase 3 trial studying the use of delamanid for treatment of MDR tuberculosis (Otsuka Trial 213, NCT ) were presented at the 48th Union World Conference on Lung Health in October, 2017 (Guadalajara, Mexico). The primary endpoint was time to sputum culture conversion over the first 6 months of delamanid plus optimised background regimen versus placebo and optimised background regimen. Patients in the delamanid group had a more rapid culture conversion of 6 13 days than the placebo group, with a nonsignificant p value for efficacy of The proportions of patients who had favourable treatment outcomes at 24 months were similar in both groups. Importantly, adverse events did not increase significantly in the delamanid group. Moreover, delamanid reduced the development of fluoroquinolone resistance (NCT ). Despite the disappointing results, delamanid is a specific antituberculosis medication with an excellent safety profile, making it a useful companion drug in a regimen and useful for reducing the development of resistance. Delamanid has few drug drug interactions and might be useful in patients who are co-infected with HIV, and who have a higher risk of being unresponsive to treatment than those with tuberculosis alone. Reports indicate 49,50 that treatment with delamanid and bedaquiline in combination might well be tolerated. Although WHO does not recommend this combination because of concerns that bedaquiline and delamanid, which both prolong QT, would have potential detrimental effects in patients, it recognises that physicians might require guidance and has provided recommendations, including active safety drug monitoring, which itself might assist more rapid phase 4 safety data collection. Two trials (NCT , NCT ) will study the coadministration of these two drugs. The AIDS Clinical Trials Group study 51 A5343 DELIBERATE includes three groups delamanid, bedaquiline, and a combination of the two in a shorter regimen of 24 weeks and seeks to understand whether the combination is safe and to compare the mean changes from baseline (averaged over 8 24 weeks) in QTcF when delamanid and bedaquiline are given in combination to the mean change seen when each drug is given alone. Pretomanid Pretomanid, a nitroimidazole developed by the TB Alliance, is being considered as a potential component for a pan-tuberculosis regimen for both drug-susceptible and MDR tuberculosis. The drug is being assessed in several trials for drug-susceptible and drug-resistant tuberculosis (NC-005, NC-006 STAND, NiX-TB, TB-PRACTECAL, NC- 007 ZeNiX, NC-008 SimpliciTB). Of particular note, the NC-005 trial (NCT ) is studying a combination of bedaquiline, pretomanid, and pyrazinamide for 8 weeks in patients with drug-susceptible tuberculosis, with a separate group for patients with drug-resistant tubercu losis with the addition of moxifloxacin to the regimen. The bedaquiline, pretomanid, and pyrazinamide combination had greater antimycobactericidal activity than the standard quadruple regimen. 52 This combination was exquisitely bactericidal: sputum was converted in 78% 96% of patients receiving bedaquiline, pretomanid, and pyra- zinamide with moxifloxacin at 8 weeks of treatment, Published online March 23,

8 depending on whether the M tuberculosis strain was susceptible to the drugs in the regimen. Clearance was also up to three-times faster than the comparison group on standard quadruple therapy. 52 Regimens with bedaquiline, pretomanid, and pyrazinamide, along with moxifloxacin, reduce pill burden and might be potent enough to reduce treatment duration to 3 months in total. The regimen of bedaquiline, pretomanid, and pyrazinamide with moxifloxacin could be advantageous for patients with MDR tuberculosis by offering a shorter injectable-free regimen that might be able to treat the majority of patients. The NC-008 SimpliciTB study (NCT ) will investigate a 4-month regimen of bedaquiline, pretomanid, and pyrazinamide with moxifloxacin in patients with drugsusceptible tuberculosis versus standard isoniazid, rifampicin, pyrazinamide, and ethambutol plus this combination for 6 months in patients with MDR tuberculosis. Repurposed drugs The antileprosy drug clofazimine has shown sterilising and treatment-shortening potential. A new rimino- phenazine, TBI-166, has entered phase 1 trials (table 1) and will hopefully not produce skin discolouration, a common sideeffect of clofazimine. 53 A sizeable programmatic study in Brazil used clofazimine in a standardised 2006 MDR tuberculosis regimen, replacing pyrazinamide patients were treated with clofazimine-containing regimens and 1096 with pyrazinamide-containing regimens. The clofazimine-containing regimen was found to have similar success to the pyrazinamide-containing regimen, but more patients in the clofazimine group responded to treatment and fewer were lost to follow-up. 54 Bedaquiline and clofazimine have been shown to have cross-resistance with the mutation in Rv0678, leading to increased removal of these drugs by the MmpL5 efflux pump. 55 Meta-analyses and systematic reviews of the use of carbapenems (ertapenem, imipenem, meropenem) for treatment of MDR and XDR tuberculosis on the basis of clinical necessity indicate a role for their use in tuberculosis treatment They appear very active with excellent tolerability and safety records. However, the absence of an active oral formulation and the need for the combination of amoxicillin plus clavulanic acid (which protects meropenem or carbapenem from β-lactamases) reduce the appeal of carbapenems. Faropenem (an oral penem) showed little activity in a phase 2b trial 58 despite promising hollow fibre studies This result might be due to the low oral bioavailability of faropenem sodium. 61 Future development of oral penem or carbapenem formulations could offer another solution to the need for a pan-tuberculosis regimen. 62,63 Similarly, another β-lactam, ceftazidime, combined with the new β-lactamase inhibitor avibactam, has shown encouraging preclinical results. The M tuberculosis class A β-lactamase is potently inhibited by avibactam, rendering ceftazidime active against mycobacteria. 64 Linezolid, an oxazolidinone, has shown anti mycobacterial efficacy and is included in many drug trial regimens. 65 Its toxicity profile has restricted its use beyond drug-resistant tuberculosis. In-vitro model dose-ranging studies have identified optimal linezolid doses for use in combination therapy, maximising bactericidal activity, while avoiding toxic effects. Ongoing pharmacokinetic and pharmacodynamic studies are clarifying many dosing issues associated with new or repurposed drugs. Newer regimens for drug-resistant tuberculosis Injectable-free regimens Newer treatment regimens for MDR tuberculosis are focused on assessment of injectable-free regimens to reduce the substantial toxic effects (ototoxicity and nephrotoxicity), simplify the logistics of administration of injectable drugs, and improve patient adherence. The NeXT trial (NCT ) compares a new, all oral 6 9 month regimen of bedaquiline, linezolid, levofloxacin, and pyrazinamide, with either high-dose isoniazid or ethionamide or terizidone daily, with the standard WHO treatment regimen of months, in patients with MDR tuberculosis. Shorter treatment regimens A standardised Bangladesh regimen (high-dose gati- floxacin, clofazimine, ethambutol, and pyrazinamide supplemented by prothionamide, kanamycin, and doubledose isoniazid during the 4-month intensive phase) cured 181 (87 9%, 95% CI ) of 206 people, with no relapses. 69 A further study 70 reported a bacteriologically favourable outcome in 435 (84%) of 515 people. WHO, in 2016, subsequently recommended a shorter, standardised 9 12-month regimen for people with pulmonary MDR or rifampicin-resistant tuberculosis susceptible to aminoglycosides and fluoroquinolones. Exclusion criteria include pregnancy, extrapulmonary cases, and patients who underwent previous treatment with second-line drugs. 33 The 4 6-month intensive phase includes moxifloxacin, an injectable (amikacin or kanamycin), ethionamide or prothionamide, clofazimine, high-dose isoniazid (10 mg/kg to a maximum of 600 mg a day), ethambutol, and pyrazinamide, and the 5-month continuation phase includes moxifloxacin, clofazimine, ethambutol, and pyrazinamide. 70,71 The only difference between the Bangladesh regimen and the WHO shorter regimen is the substitution of gatifloxacin for moxifloxacin. A meta-analysis 2 reported the effectiveness of this regimen for treating MDR tuberculosis, although quinolone resistance was associated with unsuccessful treatment and relapse (odds ratio 46, 95% CI 8 273). Several research centres have attempted to foresee what effect the shorter regimen would have in their setting a subject that is much debated The phase 3 STREAM Stage 1 trial 76 assessed the 2011 WHO standard MDR tuberculosis regimen (20 24 months), and compared it with the current WHO MDR tuberculosis 8 Published online March 23,

9 regimen (9 months). Although interim results suggest the more recent regimen is not non-inferior, it might be a good option for selected patients because treatment success was achieved in 78 1% of participants with the regimen compared with 80 6% in the individualised month regimen. Severe adverse events were similar in both groups, although a higher frequency of cardiac conduction disorders was observed in patients who received the shorter 9-month regimen. 76 A phase 3 STREAM Stage 2 trial (NCT ) is establishing whether bedaquiline could play a part in a shorter regimen, by comparing 6-month and 9-month all-oral bedaquiline-containing regimens against the locally used WHO-approved MDR tuberculosis regimen, and the 18-month WHO MDR tuberculosis regimen results are expected in The NiX-TB trial (NCT ) assessed a 6-month regimen of bedaquiline, pretomanid, and linezolid (600 mg twice daily). For situations in which a patient does not culture convert by month 4, the regimen is prolonged to 9 months. As of October, 2017, 109 participants were enrolled in the study, 70 of whom had completed the 6-month treatment course, with 31 reaching 6-month follow-up. The proportion of patients who have achieved a relapse-free cure to date was 26 (87%) of 30 participants, whereas early mortality was reported in four participants in the first 2 months. 65% people achieved culture conversion by week 8 and 100% by week In November, 2017, NiX-TB rolled over into the new NC-007 ZeNiX trial (NCT ), which includes a dose-ranging study for linezolid. The TB-PRACTECAL (NCT ) is an adaptive-design study assessing culture conversion at week 8, outcome, and safety of a short regimen (6 months) versus the WHO-recommended MDR tuberculosis regimen (locally used and accepted), including bedaquiline, pretomanid, and linezolid, with or without moxifloxacin or clofazimine, to treat adults with MDR or XDR tuberculosis. The endtb is an MSF and UNITAID study (NCT ) that aims to develop one to three priority regimens for the treatment of MDR and XDR tuberculosis and to increase access to bedaquiline and delamanid. The study is a phase 3 trial comparing five experimental groups with a standard-of-care control, which may include delamanid or bedaquiline. High rates of culture conversion at 6 months and low culture reversion rates at 12 months are preliminary findings. 78 Updates on tuberculosis drugs for latent infection Clinicians and patients have long desired shorter, more tolerable, and safer alternatives for treatment of latent tuberculosis infection than standard daily isoniazid for 9 months or more. In 2011, the phase 3 TBTC Study 26 (NCT ), undertaken in 7731 participants, showed non-inferiority of weekly rifapentine and isoniazid (given for 3 months) when compared with 9 months of daily isoniazid. 79 Rifapentine is still unavailable in most countries worldwide. To date, no data are available from phase 3 trials of eradication of latent infection due to drugresistant M tuberculosis, though two trials are underway assessing 6 months of daily levofloxacin versus placebo, and a large trial will soon begin assessing 6 months of daily delamanid versus 9 months of daily isoniazid, in adults and children. Drug-resistant latent tuberculosis infection is a high priority for the control of the growing drug-resistant tuberculosis threat. 80 Table 4 summarises ongoing and planned trials investigating chemoprophylaxis for individuals exposed to drug-susceptible and drug-resistant tuberculosis that are underway or will open soon. Advances and progress in host-directed therapies Effective host immunity prevents M tuberculosis from causing disease in most individuals. Waning host defence leads to increased susceptibility to disease and poor treatment outcomes as illustrated by M tuberculosis and HIV co-infection. Augmentation of beneficial immune responses might serve as useful adjunct therapy to tuberculosis drug-treatment regimens. 81 Host-directed therapy (HDT) approaches (table 5) are now a focus for use as adjunct treatment options for MDR tuberculosis, for shortening treatment duration, limiting immunopathology by modulating aberrant M tuberculosis-induced immune responses, and improving treatment outcomes. 8,81 Immunotherapy is revolutionising cancer treatment, and similar host pathways operational in tuberculosis are being investigated. Three main approaches are being taken forward for HDT as adjunct therapy for tuberculosis treatment: amplification of host immunity, modulation of inflammation to reduce lung tissue destruction, and killing or containment of M tuberculosis. Small-molecule drugs and enzymes that have therapeutic value in metabolic diseases are being investigated for their usefulness as HDTs. Metformin has been shown to augment immune effector function and reduce M tuberculosis burden in preclinical tuberculosis models. 83 Other HDTs being assessed are commonly used over-the-counter drugs that are safe and cheap, such as aspirin, indomethacin, as well as vitamins and biological compounds eg, flavonoids and stilbenoids. Therapeutic antibodies targeting cell surface molecules of M tuberculosis-infected cells, or molecules that neutralise circulating proteins detrimental to protective immunity, are being developed as HDT options for use as adjuncts with antituberculosis treatment regimens. Exosomes released by T and B lymphocytes might enhance anti-m tuberculosis immune reactivity. MHC-peptide complexes, micro RNA, and fragments of DNA, as well as apoptosis inducers such as Fas ligand, could play an overall part in immunomodulation. 84,85 Translational studies incorporating novel technologies, such as tissueembedded microchips and ex-vivo three-dimensional culture models, are underway for studying HDTs 86 (for further preclinical and translational research HDT strategies see appendix). Published online March 23,